This proposal seeks to clarify the role of TGF-alpha, EGF and TGF-beta3, and their receptors, in lung morphogenesis and in lung repair following oxygen injury. These factors mediate autocrine/paracrine signalling between the respiratory epithelium and pulmonary mesenchyme. The specific aims are based on preliminary data demonstrating that 1) expression of TGF-alpha in the respiratory epithelium of transgenic mice causes marked alveolar hypoplasia and pulmonary fibrosis; 2) that the pulmonary lesions seen in TGF-alpha expressing transgenic mice are ameliorated by the expression of the dominant/negative EGF receptor in Type Il epithelial cells; and 3) that TGF-beta1 blocks prenatal alveolarization, in association with inhibition of epithelial and mesenchymal cell differentiation. The specific aims will discern the effects of TGF-alpha, TGF-beta and receptors in embryonic and postnatal lung morphogenesis and fibrosis seeking to identify the cellular mechanisms involved in the epithelial mesenchymal cell signalling pathways involved in the pathogenesis of chronic lung disease in neonates and in adults with fibrotic lung disease. Relationships between TGF-alpha and TGF-beta mediating cell signalling, lung cell proliferation and differentiation will be assessed in transgenic mice expressing TGF-alpha and TGF-beta, the latter under conditional control of a tetracycline regulatable lung-specific transgene. Transgenic EGF-R deficient, wa-2/wa-2, and TGF-beta1 gene targeted mice, as well as transgenic mice bearing EGF-R dominant/negative and TGF-beta receptor 2 dominant/negative receptors will be used to inhibit receptor signalling in specific subsets of respiratory cells. These animal models will be used to determine the role of TGF-alpha, EGF-R, and TGF-beta in acute and chronic pulmonary oxygen injury. These studies will determine whether EGF and TGF-beta receptor pathways are involved in lung remodelling and pulmonary fibrosis in the neonatal and postnatal lung. Morphological, biochemical, immunocytochemical and physiologic studies will be used to clarify the cellular and biochemical alterations mediated by these receptor systems in developing and injured lung. Potential role of EGF and TGF-beta receptor signalling in the pathogenesis of acute and chronic lung injury (RDS and BPD) and in adults with fibrotic lung diseases (ARDS, idiopathic pulmonary fibrosis and sarcoidosis) will be established.